The impact of diagnostic delay on survival in alpha-1-antitrypsin deficiency: results from the Austrian Alpha-1 Lung Registry.

BACKGROUND: Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder that can manifest as lung disease. A delay between onset of symptoms and diagnosis of AATD is common and associated with worse clinical status and more advanced disease stage but the influence on survival is unclear. OBJECTIVE: We aimed to investigate the impact of diagnostic delay on overall survival (OS) and transplant-free survival (TS) in AATD patients. METHODS: We analysed 268 AATD patients from the prospective multi-centre Austrian Alpha-1 Lung (AAL) Registry, employing descriptive statistics, Chi-square-test as well as univariable (Kaplan-Meier plots, log-rank test) and multivariable survival analysis (Cox regression). RESULTS: The predominant phenotype was Pi*ZZ (82.1%). At diagnosis, 90.2% had an AAT level below 0.6 g/L. At inclusion, 28.2% had never smoked, 68.0% had quit smoking and 3.8% continued to smoke. Lung disease was diagnosed in 98.5%, thereof most patients were diagnosed with emphysema (63.8%) and/or chronic obstructive pulmonary disease (44.0%). Median diagnostic delay was 5.3 years (inter-quartile range [IQR] 2.2-11.5 years). In multivariable analysis (n = 229), a longer diagnostic delay was significantly associated with worse OS (hazard ratio [HR] 1.61; 95% CI 1.09-2.38; p = 0.016) and TS (HR 1.43; 95% CI 1.08-1.89; p = 0.011), independent from age, smoking status, body mass index (BMI), forced expiratory volume in one second (FEV1) and long-term oxygen treatment. Furthermore, BMI, age and active smoking were significantly associated with worse OS as well as BMI, active smoking and FEV1 were with worse TS. CONCLUSIONS: A delayed diagnosis was associated with significantly worse OS and TS. Screening should be improved and efforts to ensure early AATD diagnosis should be intensified.

Art v 1 IgE epitopes of patients and humanized mice are conformational.

BACKGROUND: Worldwide, pollen of the weed mugwort (Artemisiavulgaris) is a major cause of severe respiratory allergy, with its major allergen, Art v 1, being the key pathogenic molecule for millions of patients. Humanized mice transgenic for a human T-cell receptor specific for the major Art v 1 T-cell epitope and the corresponding HLA have been made. OBJECTIVE: We sought to characterize IgE epitopes of Art v 1-sensitized patients and humanized mice for molecular immunotherapy of mugwort allergy. METHODS: Four overlapping peptides incorporating surface-exposed amino acids representing the full-length Art v 1 sequence were synthesized and used to search for IgE reactivity to sequential epitopes. For indirect mapping, peptide-specific rabbit antibodies were raised to block IgE against surface-exposed epitopes on folded Art v 1. IgE reactivity and basophil activation studies were performed in clinically defined mugwort-allergic patients. Secondary structure of recombinant (r) Art v 1 and peptides was determined by circular dichroism spectroscopy. RESULTS: Mugwort-allergic patients and humanized mice sensitized by allergen inhalation showed IgE reactivity and/or basophil activation mainly to folded, complete Art v 1 but not to unfolded, sequential peptide epitopes. Blocking of allergic patients' IgE with peptide-specific rabbit antisera identified a hitherto unknown major conformational IgE binding site in the C-terminal Art v 1 domain. CONCLUSIONS: Identification of the new major conformational IgE binding site on Art v 1, which can be blocked with IgG raised against non-IgE reactive Art v 1 peptides, is an important basis for the development of a hypoallergenic peptide vaccine for mugwort allergy.

Adrenomedullin and elements of orthostatic competence after 41 h of voluntary submersion in water as measured in four healthy males.

Four men established a new score (Guinness Book of Records) by staying submersed in thermoneutral water (average diving depth 2.5 m) for 41 h without sleeping. The aim of this study is to measure circulating hormones together with plasma mass density and total protein concentration as indices of plasma volume change to test the hypotheses that (1) blood volume and related hormones are influenced by prolonged water submersion the same way as observed after short-term water immersion, and (2) plasma adrenomedullin levels change in an opposite fashion as with orthostatic stimulation. We also studied effects on cortisol and testosterone levels. Water submersion led to a 19% increase in plasma protein concentration and a 2.5 g/l rise in plasma mass density, corresponding to a 15.6+/-1.1% plasma volume decrease (P=0.00). We therefore individually corrected (c) the observed post-submersion hormone values for plasma volume contraction. Based on this correction, we found a rise of plasma adrenomedullin from 7.9+/-0.9 to 12.5(c)+/-2.3 pg/ml. Aldosterone rose from 123+/-14 to 186(c)+/-24 ng/ml (P=0.029); plasma renin activity increased in all four persons but the type I error was >0.05. Plasma testosterone decreased from 3.5+/-0.4 to 2.2(c)+/-0.6 ng/ml (P=0.009) while plasma cortisol stayed unchanged. The daily salivary cortisol rhythm was preserved. We conclude that long-term water submersion has endocrine as well as plasma volume effects that are opposite to those seen after short-term immersion, and which increases plasma adrenomedullin. Circadian cortisol rhythm seems to be conserved even under extreme circumstances as those of this study.

Fractionated intraluminal HDR 192Ir brachytherapy as palliative treatment in patients with endobronchial metastases from non-bronchogenic primaries.

AIM: To evaluate the efficacy of iridium-192 high-dose rate (HDR) endobronchial brachytherapy for the palliation of symptoms caused by endobronchial metastases of non-bronchogenic primaries. PATIENTS AND METHOD: Between 1991 and 1998, eleven patients (female n = 3, male n = 8; age: median 66 years, range 44-81 years) underwent intraluminal HDR brachytherapy for histologically confirmed endobronchial metastases from non-pulmonary primary tumors of various sites like urogenital tract (n = 5), gastrointestinal tract (n = 3), ear/nose/throat (n = 2) and breast (n = 1). The median time between diagnosis of the primary non-bronchogenic tumor and histopathological diagnosis of the endobronchial metastases was 39 months, range 1-99 months. A total dose of 15-20 Gy was delivered in three to four fractions of 5-6 Gy once a week. No palliative chemotherapy was added. RESULTS: Median follow-up after palliative brachytherapy was 15 months (range 1.4-59 months). Objectively, complete endoscopic response was observed in three (27%) patients, and in five (46%) others partial opening of the initially obstructed airway was achieved. Treatment was judged unsuccessful in three (27%) patients. No patient showed up with local progression. At date of analysis five patients were alive with documented residual tumor (80%) or complete response (20%). Relief of symptoms occurred in the vast majority of patients (n = 8, 73%). CONCLUSION: HDR intraluminal brachytherapy palliates symptoms in patients suffering from endobronchial metastases of non-pulmonary primary tumors. The applied treatment is a safe, effective and well tolerated palliative procedure leading to an improved patient quality of life.